Treatment of wounds

ABSTRACT

THE TREATMENT OF WOUNDS BY ORALLY ADMINISTERING A PHARMACEUTICAL PREPARATION CONTAINING A COMPOUND OF THE FORMULA 1   2-(R1O-),3-(HO-),4-(R3O-),5-(R6O-CH2-CH(-OR5)-)-TETRAHYDRO   FURAN I   WHEREIN R1 IS HYDROGEN OR ALKYL WITH UP TO 7 CARBON ATOMS, AND R3, R5 AND R6 EACH INDEPENDENTLY IS HYDROGEN, ALKYL WITH UP TO 7 CARBON ATOMS, ALKENYL WITH UP TO 7 CARBON ATOMS, BENZYL, HALOGENO-BENZYL, (C1-C7-ALKYL)BENZYL, (C1-C7-ALKOXY)-BENZYL OR TRIFLUOROMETHYL-BENZYL.

United States Patent (3 ABSTRACT OF THE DISCLOSURE The treatment ofwounds by orally administering a pharmaceutical preparation containing acompound of the formula I Ruo i H \CHOR1 wherein R is hydrogen or alkylwith up to 7 carbon atoms, and R R and R each independently is hydrogen,alkyl with up to 7 carbon atoms, alkenyl With up to 7 carbon atoms,benzyl, halogeno-benzyl, (C C -alkyl)- benzyl, (C C -alkoXy)-benzyl ortrifluoromethyl-benzyl.

DESCRIPTION OF THE INVENTION The invention relates to the treatment ofwounds which is characterized by orally administering a pharmaceuticalpreparation containing a compound of the formula I RuOCHg R50 H O HOCHOR;

CHORrCHOH wherein R is hydrogen or alkyl with up to 7 carbon atoms, andR R and R each independently is hydrogen, alkyl with up to 7 carbonatoms, alkenyl with up to 7 carbon atoms, benzyl, halogeno-benzyl, (C -C-alkyl)- benzyl, (C C -alkoXy)-benzyl or trifluoromethyl-benzyl.

A residue R R R and R being alkyl with up to 7 carbon atoms and C -C-alkyl in a residue R R and R being (C -C -alkyn-benzyl is methyl,ethyl, propyl or isopropyl, and straight or branched butyl, pentyl,hexyl or heptyl bonded in any desired position.

A residue R R and R being alkenyl with up to 7 carbon atoms isespecially for example an allyl and methallyl radical.

Halogen in a halogeno-benzyl radical R R and R is fluorine, bromine,iodine and especially chlorine.

C -C alkoxy in a residue R R and R being (C -C alkoxy)-benzyl is ethoxy,n-propoxy, iso-propoxy and straight or branched butyloxy, pentyloxy,hexyloxy or heptyloxy and especially methoxy.

The compounds of the formula I are mixtures of anomers or czor,B-anomers.

It has been found that orally administering a pharma ceuticalpreparation as defined above is helpful for the healing of wounds. Thus,oral administration of a pharmaceutical preparation as defined aboveresults (a) in a stimulation of the formation of granulation tissue, ascan be shown in the wound granulation test according to Rudas[Arzneimittel Forschung, 10, 226-229 (1960)] on rats by oraladministration of about 10002000 mg./kg./ day of a compound of theformula I, (b) in an acceleration of the wound diameter reduction, ascan be shown in the epithelisation test according to Wilhelmi [GiornaleItal. Chemioter., 1, 111-116 (1954) and Salicylates, In-

ternat. Sympos., London, 1962, Churchill LTD, London, 176-185 (1963)] onrats by oral administration of about 1000 mg./kg./day of a compound ofthe formula I, and (c) in an increase of the wound breaking strength, ascan be shown in the tensile strength test according to Sixt et a1.[Arzneimittel Forschung, 18, 1460-1462 (1969)] on rats by oraladministration of about 300-1000 mg./kg./ day of a compound of theformula I.

According to a preferred embodiment of the invention the treatment ofwounds is performed by orally administering a pharmaceutical preparationcontaining a compound of the formula I, wherein R is alkyl with up to 4carbon atoms, and R R and R each independently is alkyl with up to 4carbon atoms, alkenyl with up to 4 carbon atoms, benzyl,halogeno-benzyl, (C -C -alkyl)- benzyl, (C C -alkoXy)-benzyl ortrifluoromethyl-benzyl.

Above all to be mentioned is said treatment using a pharmaceuticalpreparation containing a compound of the formula I, wherein R is alkylwith up to 4 carbon atoms, especially methyl or ethyl, and one, two orall three of R R and R are benzyl, chloro-benzyl, methyl-benzyl,methoxy-benzyl or trifluorometbyl-benzyl and the remaining are alkylwith up to 4 carbon atoms or alkenyl with up to 4 carbon atoms,especially methyl, ethyl, n-propyl or allyl.

Compounds of the formula I to be especially highlighted are ethyl 3 On-propyl-5,6-di-O-(4-chlorobenzyl)-D- glucofuranoside and above allethyl-3,5,6-tri-O-benzyl-D- glucofuranoside.

According to the invention the pharmaceutical preparations as definedabove are administered orally to a warmblooded animal in dosessufficient for improving the healing of wounds. Thus, a warm-bloodedanimal of about kg. body weight is orally treated with a daily dose ofabout 400 mg. to about 1200 mg, above all of about 600 mg. to about 1200mg. of a compound of the formula I, especially one of the abovepreferably mentioned compound of the formula I. The compound of theformula I is preferably administered in the form of a pharmaceuticalpreparation as defined above.

According to a preferred method of treatment of wounds a pharmaceuticalpreparation is orally administered containing as compound of the formulaI ethyl-3- O-n-propyl-S,6 di O (4-chlorobenzyl)-D-glucofuranoside orethyl-3,5,6-tri-O-benzyl-D-glucofuranoside in doses of about 400 mg. toabout 1200 mg, especially of about 600 mg. to about 1200 mg. per day ofsaid compounds of the formula I.

Oral administration of a pharmaceutical preparation as defined above canbe effected after a Wound is created in a warm-blooded animal, e.g. byaccident or by operation, but can also be effected before an operationis performed, e.g. up to several days, such as 4 days before anoperation is performed.

The pharmaceutical preparations as defined above contain a compound ofthe formula I either without any carrier or preferably in admixture orconjunction with a pharmaceutically acceptable carrier for liquid orsolid preparations.

A pharmaceutically acceptable carrier is for example concentrated milk,a suitable oil, such as olive oil, polyethyleneglycol orcarboxymethylcellulose. Such a pharmaceutically acceptable carrier isespecially suitable for liquid pharmaceutical preparations.

A pharmaceutically acceptable: carrier especially suitable for solidpharmaceutical preparations is for example described in US. Pat.3,594,474. Accordingly, a free flowing granular material which caneasily be processed into solid oral administration forms can be obtainedin a simple manner if an oily or liquid compound of the formula I ismixed with a film-forming agent and a lower alkanol such as methanol,isopropanol or primaril etha- 1101, worked into a plastic mass withmagnesium trisilicate, if desired together with a further absorbent suchas colloidal silica or cellulose, especially microcrystalline cellulose,and the mass granulated whilst drying it, for example with Warm air.

As film-forming agents there are preferably used those which also act asbinding agents, especially shellac, polyacrylic or methacrylicderivatives, especially their st rs, carbowaxes, polyvinyl derivativessuch as polyvinyl acetates, or primarily polyvinyl pyrrolidones, forexample polyvinylpyrrolidone or polyvinylpyrrolidone-polyvinyl acetatecopolymers. Further possible film-forming agents are alcohol-soluble orwater-soluble cellulose derivatives, especially celluloseacetate-phthalate, hydroxypropylmethylcellulose, ethylcellulose,ethyl-hydroxyethyl-cellulose, hydroxypropyl-cellulose,carboxymethylcellulose and/or carboxyethylcellulose.

The process is preferably elTected by dissolving the filmforming agentin the lower alkanol, mixing the furanoside with this solution, andmixing this solution with the magnesium trisilicate and optionally theadsorbent to give a plastic mass, and drying and granulating the latterin the usual manner. When mixing the solution of the furanoside withmagnesium trisilicate, the sugar is adsorbed on the latter.

The film-forming agent is preferably used in a concentration of 0.2 to20, especially 1-5 and primarily 2-4, parts by weight relative to 10parts by weight of furanoside. The magnesium trisilicate is used in anamount which permits adsorption of the furanoside, especially in aconcentration of -20, preferably 8-15 or primarily about -12 parts byweight calculated relative to 10 parts by weight of furanoside. Thefurther adsorbent is used in an amount of 1-20, preferably 1-10 andprimar ly 4-6, parts by weight calculated relative to 10 parts by weightof furanoside.

The granular material obtained is stable for prolonged periods even at ahigher temperature, for example 60, and can be easily processed into anydesired oral administration form.

The granular material is suitable for the manufacture of solid oraladministration forms such as tablets, pushfit capsules or primarilydrages. These may be obtained in the usual manner.

EXAMPLE 1 10 parts by weight ofethyl-3,5,6-tri-O-benzyl-D-glucofuranoside, 10 parts by weight ofmagnesium trisilicate, 5 parts by weight of colloidal silica and 2.5parts by Weight of polyvinylpyrrolidone (PVP).

The PVP is dissolved in a fourfold amount of alcohol and mixed with theethyl-3,5,6-tri-O-benzyl-D-glucofuranoside. This solution is processedinto a paste with the magnesium trisilicate in a suitable apparatus andis kneaded with colloidal silica to give a plastic mass. It is thengranulated and dried in the usual manner.

5.45 parts by weight of granular material are mixed with 2.0 parts byweight of starch, 1.7 parts by weight of talc and 0.3 part by weight ofmagnesium stearate and processed into pressed blanks weighing 585 mg.and containing 200 mg. of ethyl-3,5,-6-tri-O-benzyl-D-glucofuranoside.

In order to mask the bad taste, the pressed blanks are, after coatingwith a protective lacquer, converted in the usual manner with sugar intodrages.

The daily oral dose for a warm-blooded animal of about 75 kg. bodyweight is about 2 to 6 drages.

EXAMPLE 2 10 parts by weight of preparation of ethyl-3-O-npropyl 5,6di-O-p-chlorobenzyl-D-glucofuranoside, 14 parts by weight of magnesiumtrisilicate, 5 parts by weight of colloidal silica and 2.5 par-ts byweight of polyvinylpyrrolidone.

The PVP is dissolved in the fourfold quantity of alcohol and mixed withthe furanoside. This solution is processed into a paste with magnesiumtrisilicate in a suitable apparatus and kneaded with colloidal silica togive a plastic mass. The mass is granulated and dried in the usualmanner.

31.5 parts by weight of granular material are mixed with 0.8 part byweight of starch, 1.55 parts by weight of microcrystalline cellulose,1.05 parts by weight of talc and 0.15 part by weight of magnesiumstearate and processed into pressed blanks of 350 mg.=l00 mg. offuranoside.

These cores are given a protective lacquer in the usual manner and thenconverted into drages with sugar.

The daily oral dose for a warm-blooded animal of about 75 kg. bodyWeight is about 6-12 drages.

EXAMPLE 3 10 parts by weight ofethyl-3,5,G-tri-O-benzyl-D-glucofuranoside, 10 parts by weight ofmagnesium trisilicate, 5 parts by weight of colloidal silica, 0.5 partby weight of polyvinylpyrrolidone, and 2 parts by weight ofmicrocrystalline cellulose.

The PVP is dissolved in a fourfold amount of alcohol and mixes with theethyl-3,5,6-tri-O-benzyl D glucofuranoside. This solution is processedinto a paste with the magnesium trisilicate in a suitable apparatus andis kneaded with colloidal silica to give a plastic mass. It is thengranulated and dried in the usual manner.

5.45 parts by weight of granular material are mixed with 2.0 parts byweight of starch, 1.7 parts by weight of talc and 0.3 part by weight ofmagnesium stearate and processed into pressed blanks weighing 585 mg.and containing 200 mg. of ethyl-3,5,6-tri-O-benzyl D glucofuranoside.

In order to mask the bad taste, the pressed blanks are, after coatingwith a protective lacquer, converted into drages with sugar in the usualmanner.

The daily oral dose for a warm-blooded animal of about 75 kg. bodyweight is about 6-12 drages.

What is claimed is:

1. A method of treating wounds in a warm-blooded animal which ischaracterized by orally administering to said animal an eifective woundhealing amount of a compound of the formula R OCH;

R50 H O CHOR3-CHOH wherein R is hydrogen or alkyl with up to 7 carbonatoms, and R R and R each independently is hydrogen, alkyl with up to 7carbon atoms, alkenyl with up to 7 carbon atoms, benzyl,halogeno-benzyl, (C Cr,-alkyl)-benzyl, (C C -alkoxy)-benzyl ortrifluoromethyl-benzyl.

2. The method of claim 1, wherein R is alkyl with up to 4 carbon atoms,and R R and R each independently is alkyl with up to 4 carbon atoms,alkenyl with up to 4 carbon atoms, benzyl, halogeno-benzyl, (C C-alkyl)- benzyl, (C -C -alkoxy)-benzyl or trifluoromethyl-benzyl.

3. The method of claim 1, wherein R is alkyl with up to 4 carbon atoms,and one, two or all three of R R and R are benzyl, chloro-benzyl,methyl-benzyl, methoxybenzyl or trifluoromethyl-benzyl and the remainingare alkyl with up to 4 carbon atoms or alkenyl with up to 4 carbonatoms.

4. The method of claim 1, wherein the compound is ethyl 3O-n-propyl-5,6-di-O-(4-chlorobenzyl)-D-glucofuranoside.

5. The method of claim 1, wherein the compound isethyl-3,5,6-tri-O-benzy1-D-glucofuranoside.

6. The method of claim 1, wherein a daily dose of 400-1200 mg. isadministered to a warm-blooded animal of about 75 kg. body weight.

7. The method of claim 1, wherein the compound is employed without anycarrier.

8. The method of claim 1 wherein the compound is employed in admixtureor conjunction with a pharmaceutically acceptable carrier.

6 References Cited UNITED STATES PATENTS 3,157,634 11/1964 Druey et a1424180 3,538,077 11/1970 Rossi 424-180 FOREIGN PATENTS 2,015,760 3/1971Germany 424-180 ALBERT T. MEYERS, Primary Examiner F. E. WADDELL,Assistant Examiner

